Clinical Oncology 30 (2018) 504e506

Contents lists available at ScienceDirect

Clinical Oncology
journal homepage: www.clinicaloncologyonline.net

Radiation Therapy in Ovarian Cancer: An Overview and Future

Directions
M. McCormack
Department of Oncology, University College London Hospital, London, UK

Received 1 June 2018; accepted 1 June 2018

Abstract
Clear cell cancer of the ovary is a rare and aggressive subtype. There is a general paucity of data from randomised trials to inform the most appropriate approach
to adjuvant therapy. Retrospective data has highlighted an improvement in disease free survival with the addition of whole abdominal radiotherapy. This
approach merits further exploration in a randomised clinical trial.
Ó 2018 Published by Elsevier Ltd on behalf of The Royal College of Radiologists.

Key words: Clear cell; ovary; radiotherapy

Introduction influenced by presurgical capsular rupture, the presence of

Epithelial ovarian cancer (EOC) is the most common
gynaecological cancer in women in the UK, with over 7000
new cases diagnosed annually. EOC is now known to
comprise at least five different pathological subtypes: high
grade serous, low grade serous, clear cell, endometrioid and
mucinous. Ovarian clear cell cancer (OCCC) was formally
defined as a distinct subtype of EOC by the World Health
Organization in 1973. It is a rare subtype, accounting for
5e25% of all cases of ovarian cancer worldwide and is more
common in Asian women [1]. Traditionally, OCCC has been
treated exactly the same as other subtypes of EOC, yet
differences in the stage at presentation, the pattern of
relapse, the response to chemotherapy and its prognosis
highlight the differences between OCCC and the more
common high grade serous type. In patients with OCCC,
about 80% present with early stage (International Federa-
tion of Gynecology and Obstetrics [FIGO] I/II) disease, in
contrast to high grade serous, where up to 75% present with
stage III/IV disease [2]. Despite the earlier stage at presen-
tation, debulking surgery and adjuvant chemotherapy, the
outcome for patients with stage I/II OCCC is not universally
favourable. Indeed, within FIGO stage I this is adversely
E-mail address: mary.mccormack2@nhs.net.
disease on the surface of the ovary and positive cytology
(namely substage Ic2/3). Progression-free survival (PFS) at
5 years for patients with stage IA is over 95% [3,4], whereas
it is only 44e57% in patients with stage Ic2/3 and stage II
disease [5e7], despite the use of taxane-based adjuvant
chemotherapy.
There is no clear evidence from randomised trials to
underpin the current approach of surgery followed by
standard ovarian cancer chemotherapy and guidelines are
based on extrapolation of results of treatment from EOC
trials where the OCCC subtype typically accounts for less
than 3% of the subjects [8]. Furthermore, most of the specific
data on OCCC treatment are derived from retrospective
single institution studies, mainly from Japan and Korea.
There is one published international randomised phase III
trial in OCCC led by the Japanese Gynaecology Oncology
Group (JGOG 3017). The trial was designed to compare the
efficacy and safety of two different platinum-containing
regimens (carboplatin/taxane versus irinotecan/cisplatin).
At a median follow-up of 44 months there was no signifi-
cant difference in 2 year PFS between the two combina-
tions. Although over 60% of patients had stage I disease, the
PFS rate at 2 years was only 73e77% [9]. A post-hoc analysis
of patients of these early stage patients showed that the
pelvis was the first site of relapse in up to 58% (Okamoto,

https://doi.org/10.1016/j.clon.2018.06.001
0936-6555/Ó 2018 Published by Elsevier Ltd on behalf of The Royal College of Radiologists.
 M. McCormack / Clinical Oncology 30 (2018) 504e506
personal communication, 2016). This has also been noted in
other studies [10].
Prognosis post-recurrence is dismal, with response rates
of less than 10% to commonly used chemotherapy drugs
[5,11]. Approaches beyond conventional chemotherapy
therefore warrant further exploration and trials of targeted
agents are ongoing.
Ovarian cancer and radiotherapy
In the past, radiotherapy was frequently used in the
management of patients with ovarian cancer. It was the
mainstay of adjuvant treatment for many years, but was
replaced by cisplatin almost three decades ago. Neverthe-
less, it remains a useful, if little used, strategy in patients
with chemoresistant/refractory disease. Indeed, retrospec-
tive studies have shown that radiotherapy can lead to a
prolonged disease-free survival and potentially result in
cures for selected patients with locoregionally relapsed or
persistent disease despite chemotherapy. The largest series
from the MD Anderson [12] showed 5 year overall survival
and PFS rates of 40% and 24%, respectively, in heavily pre-
treated ovarian cancer patients who received involved field
radiotherapy. However, the 5 year overall survival and PFS
rates for the clear cell subgroup were 88% and 75%,
respectively.
In vitro studies using a newly established OCCC cell line
(TAYA) derived from a patient with relapsed disease
showed that these cells were sensitive to radiation with an
ID50 of 1.8 Gy, similar to their previous observations in
cervical cancer cell lines [13]. However, IC50 (nM) values
>10 000 for cisplatin and gemcitabine clearly showed these
cell lines to be resistant to chemotherapy.
In a retrospective analysis of population-based data from
the British Columbia Cancer Agency, Hoskins et al. [7]
reviewed the outcome of patients with stage I/II OCCC af-
ter surgery and adjuvant therapy. This analysis was based
on 241 patients treated within four centres in British
Columbia between 2000 and 2008, thereby limiting the
review to patients treated in the ‘taxane era’. The British
Columbia protocol consisted of three cycles of carboplatin
and paclitaxel chemotherapy followed by radiotherapy to
the whole abdomen and pelvis with a default position of six
cycles of the same chemotherapy. However, the oncologists
were consistent in their use or not of irradiation, with some
opting to offer chemotherapy alone. In patients with stage
Ia/b and Ic1 disease there was no discernible benefit to
radiotherapy. However, in those with stage Ic2/3 and II
there was a statistically significant improvement in disease-
free survival of 20% at 5 years (relative risk (RR) 0.54,
P ¼ 0.02) after three cycles of chemotherapy and radio-
therapy compared with chemotherapy alone.
Another retrospective review of outcome in 215 patients
with early stage EOC after surgery and radiotherapy iden-
tified FIGO stage, histopathological subtype and tumour
grade as independent prognostic factors for recurrence-free
survival [14]. The best outcome was in the subgroup of 24
505
patients with OCCC, where the 5 year survival was 80%
compared with 60% for the entire group. Dinniwell et al.
[15], in their small case series of 29 EOC patients treated
with postoperative platinum/taxane chemotherapy and
radiotherapy, also observed a similar improvement in
outcome for those patients with OCCC and endometrioid
tumours. The 4 year disease-free survival was 77% in the
OCCC/endometrioid cohort and 27% in those with serous
histology. Collectively these small studies support the view
that the outcome of OCCC is different from other EOC sub-
types, and they lend credence to the hypothesis that
radiotherapy may reduce the risk of relapse in a select
group of patients with early stage OCCC.
These studies used whole abdominal radiation with the
abdominal cavity usually receiving doses in the region of
22.5 Gy in 22 fractions or about half the total dose to the
pelvis. It could therefore be argued that such a low dose
may have minimal impact on any residual microscopic
disease and therefore should be abandoned. Furthermore,
comprehensive surgical staging as used today minimises
the risk of leaving occult disease in the abdomen and im-
proves the chances that patients with stage I/II disease are
truly early stage.
Conclusion
Given the uncertainty about clinical management, a
frontline study in OCCC is long overdue. Radiotherapy,
which has been shown in small studies to improve the
outcome of early OCCC, is a therapeutic strategy that should
be explored in this disease, particularly as the pelvis is the
first site of relapse in over half the patients. Advances in the
planning and delivery of radiotherapy [16], which have led
to a reduction in morbidity, make this a very attractive,
affordable and widely available treatment modality in the
present day.
References
[1] Okamoto A, Glasspool RM, Mabuchi S, Matsumura N,
Nomura H, Itamochi H, et al. Gynecologic Cancer InterGroup
(GCIG) consensus review for clear cell carcinoma of the ovary.
Int J Gynecol Cancer 2014;24(9 Suppl. 3):S20eS25.
[2] Kobel M, Kalloger SE, Santos JL, Huntsman DG, Blake Gilks C,
Swenerton KD. Tumour type and substage predict survival in
stage I and II ovarian carcinoma: insights and implications.
Gynecol Oncol 2010;116:50e56.
[3] Takano M, Kikuchi Y, Yaegashi N, Kuzuya K, Ueki M, Tsuda H,
et al. Clear cell carcinoma of the ovary: a retrospective mul-
ticentre experience of 254 patients with complete surgical
staging. Br J Cancer 2006;94(10):1369e1374.
[4] Mizuno M, Kikkawa F, Shibata K, Kajiyama H, Suzuki T, Ino K,
et al. Long-term prognosis of stage I ovarian carcinoma.
Prognostic importance of intraoperative rupture. Oncology
2003;65(1):29e36.
[5] Takano M, Sugiyama T, Yaegashi N, Sakuma M, Suzuki M,
Saga Y, et al. Low response rate of second-line chemotherapy
for recurrent or refractory clear cell carcinoma of the ovary: a
506 M. McCormack / Clinical Oncology 30 (2018) 504e506
retrospective Japan Clear Cell Carcinoma Study. Int J Gynecol
Cancer 2008;18(5):937e942.
[6] Chan JK, Tian C, Monk BJ, Herzog T, Kapp DS, Bell J, et al.
Prognostic factors for high-risk early-stage epithelial ovarian
cancer: a Gynecologic Oncology Group study. Cancer 2008;
112(10):2202e2210.
[7] Hoskins PJ, Le N, Gilks B, Tinker A, Santos J, Wong F, et al. Low-
stage ovarian clear cell carcinoma: population-based outcomes
in British Columbia, Canada, with evidence for a survival benefit
as a result of irradiation. J Clin Oncol 2012;30(14):1656e1662.
[8] Mackay HJ, Brady MF, Oza AM, Reuss A, Pujade-Lauraine E,
Swart AM, et al. Prognostic relevance of uncommon ovarian
histology in women with stage III/IV epithelial ovarian cancer.
Int J Gynecol Cancer 2010;20(6):945e952.
[9] Sugiyama T, Okamoto A, Enomoto T, Hamano T, Aotani E,
Terao Y, et al. Randomized phase III trial of irinotecan plus
cisplatin compared with paclitaxel plus carboplatin as first-
line chemotherapy for ovarian clear cell carcinoma:
JGOG3017/GCIG Trial. J Clin Oncol 2016 August 20;34(24).
[10] Mizuno M, Kajiyama H, Shibata K, Mizuno K, Yamamuro O,
Kawai M, et al. Adjuvant chemotherapy for stage I ovarian
clear cell carcinoma: is it necessary for stage IA? Int J Gynecol
Cancer 2012;22(7):1143e1149.
[11] Crotzer D, Sun C, Coleman R, Wolf J, Levenback C,
Gershenson D. Lack of effective systemic therapy for recurrent
clear cell carcinoma of the ovary. Gynecol Oncol 2007;105(2):
404e408.
[12] Brown AP, Jhingran A, Klopp AH, Schmeler KM, Ramirez PT,
Eifel PJ. Involved-field radiation therapy for locoregionally
recurrent ovarian cancer. Gynecol Oncol 2013;130(2):
300e305. https://doi.org/10.1016/j.ygyno.2013.04.469.
[13] Saga Y, Suzuki M, Mizukami H, Urabe M, Fukushima M,
Ozawa K, et al. Enhanced expression of thymidylate synthase
mediates resistance of uterine cervical cancer cells to radia-
tion. Oncology 2002;63(2):185e191.
[14] Skirnisdottir I, Garmo H, Wilander E, Holmberg L. Borderline
ovarian tumors in Sweden 1960e2005: trends in incidence
and age at diagnosis compared to ovarian cancer. Int J Cancer
2008;123(8):1897e1901. https://doi.org/10.1002/ijc.23724.
[15] Dinniwell R, Lock M, Pintilie M, Fyles A, Laframboise S,
Depetrillo D, et al. Consolidative abdominopelvic radio-
therapy after surgery and carboplatin/paclitaxel chemo-
therapy for epithelial ovarian cancer. Int J Radiat Oncol Biol
Phys 2005;62(1):104e110.
[16] Klopp AH, Yeung AR, Deshmukh S, Gil KM, Wenzel L,
Westin SN, et al. A phase III randomized trial comparing
patient-reported toxicity and quality of life (QOL) during
pelvic intensity modulated radiation therapy as compared to
conventional radiation therapy; Time C trial. Int J Radiat Oncol
Biol Phys 2016;96(2):S3.